1. Field of the Invention
This invention relates generally to drug compositions or formulations which have the capability of eliciting specific responses from cellular receptors and, specifically, to those optional compositions/formulations which prevent desensitization of such receptors.
2. Discussion of Relevant Art
Throughout this disclosure, I shall use terms with their generally accepted meanings and, on occasion, supplement those meanings as indicated in order to clarify a particular facet of my invention by concentrating on a specific relationship or agenda that is normally generalized by use of the term.
An agonist is a substance/drug that has affinity for and stimulates physiologic activity at cell receptors that are normally stimulated by naturally occurring substances. As used throughout, an agonist is such a substance/drug that produces a maximal or nearly maximal response, whereas an antagonist is a substance or molecule that produces no response, but can block the action of the drug-agonist. A partial agonist produces a moderate response and can also block the response of the receptor to the agonist-drug. A competitive antagonist is a substance which competes with the agonist for the receptor, but produces no response.
Present theories of receptor activation calculate the response of a receptor as some function of an agonist-receptor complex. There have been several modifications and criticisms of receptor theory (see, for example Keen, M.; Testing Models of agonist for G-Protein Coupled Receptors: Trends Pharmacol. Sci. 12, 371-374, 1991), but none of these treatments examined the discrete change induced by ligand binding to two equilibrium states of a receptor and, consequently, no one has developed the instant (and exacting) method for determining actual drug compositions/formulations which effectively prevent desensitization of cellular receptors that are normally and incipiently responsive to a host of agonists. Careful experimental investigations of several different receptor systems have revealed that receptor theory fails to describe the observed responses in a number of cases. Also, the phenomenon of rapid desensitization has been difficult to model by modern receptor theories. Originally many of these experimental observations were reported in 1957 by del Castillo and Katz in their pioneering work on desensitization (del Castillo, J. and Katz, B. Proc. Roy. Soc. Lond. 146, 369-381, 1957). The present theories are inadequate for at least two fundamental reasons; first, they fail to describe experimental observations except for limited cases and second, they offer only a xe2x80x9cblack boxxe2x80x9d description instead of a physicochemical explanation for receptor response.
In 1991, Geoffrey et al. found that competitive antagonists of a glutamate receptor decreased the desensitization of the receptor (See Geoffrey, M., et al. Molecular Pharmacology 39, 587-591; 1991). They concluded, in this study, that such paradoxical behavior could not be described by the current theories of pharmacologic action deriving from (for example) experimental observations first recorded in 1957 by del Castillo and Katz performing their pioneering work on desensitization. Until most recently, no theory has been able to adequately explain how the behavior observed by Geoffrey et al. occurs; and, the utility of mixing competitive antagonists (or partial agonists) with agonists accurately and, therefore, efficiently to prevent receptor desensitization has been all but overlooked.
Other articles which show the utility (in vivo) of using antagonist/agonist compositions, to prevent receptor desensitization, are extant. One such article is xe2x80x9cAntitachyphylactic Effects of Progesterone and Oxytocin on Term Human Myometrial Contractile Activity In Vitroxe2x80x9d by Xin Fu, MD, Masoumeh Rezapour, MD, Mats Lxc3x6fgren, MD, PhD, Ulf ulmsten, MD, PhD, and Torbjxc3x6rn Bxc3xa4ckstrxc3x6m, MD, PhD, all of the Department of Gynecology and Obstetrics, University Hospital, Uppsala, Sweden and published in Obstetrics and Gynecology (1993; 82: 532-8). Therein, Xin Fu et al. conclude that a quantum of an antagonist, progesterone, is observed to reverse the tachyphylaxis (desensitization) to oxytocin (agonist) of human myometrium. No quantification methodology is suggested for arriving at proper dosages of the antagonist for consistently achieving this reversal, however.
Another disclosure is of certain importance in the quest for in vivo studies to support modeling investigational techniques in drug research: xe2x80x9cBeta1 and Beta2 Adrenoceptors in the Human Heart: Properties, Function, and Alterations in Chronic Heart Failurexe2x80x9d by Otto-Erich Brodde of Bio-chemisches Forschungslabor, Medizinische Klinik and Poliklinik, Abteilung fur Nieren-und Hochdruckkrankheiten, Universitxc3xa4tsklinikum, Essen, Germany. (Pharmacological Review, 1991, Vol. 43, No. 2). This is a detailed study on chronic heart failure which discusses a recognized utility of using Beta-AR (beta-adnergic receptor) antagonists for patients in certain types of heart failure (pp. 228-230) and which hypothesizes that such work by occupying Beta-ARs and prevent desensitization of cardiac Beta-ARs (see p.233 and references therein). No further information is detailed which would inform one of ordinary skill how to quantify the portions of antagonists necessary to fully retard i.e., prevent xe2x80x9cdown-regulationxe2x80x9d (desensitization, ibid p. 233) of Beta-ARs. As recently as Jul. 24, 1994, the instant inventor presented his work xe2x80x9cA Novel Biophysical Model for Receptor Activationxe2x80x9d (R. Lanzara, CUNY, New York and Bio-Balance, Inc., New York, N.Y.) to the XIIth International Congress of Pharmacology at Montrxc3xa9al, Quxc3xa9bec, Canada. Also presented was a paper published by him concerning Weber""s Law (xe2x80x9cWeber""s Law Modeled by the Mathematical Description of a Beam Balancexe2x80x9d, Mathematical Biosciences, 122:89-94 (1994)). These works are included for their teachings on the instant concept, methods of calculation to provide quanta of antagonist: agonist necessary for achieving the objectives of the invention and demonstrate objectively by use of in vivo empirical studies that the invention is a substantial improvement to the prior art and a significant advancement in the field.
3. Incorporation by Reference
The instant invention, being novel in its approach to solving the universally felt problem of drug receptor desensitization, is best appreciated with a thorough consideration of the works of the inventor and others. To this end, the following of the aforementioned works: Geoffroy et al. xe2x80x9cReduction of Desensitization of a Glutamate Ionotropic Receptor by Antagonistsxe2x80x9d Molecular Pharmacology 39: 587-91 (1991); Xin Fu et al., xe2x80x9cAntitachyphylactic Effects of Progesterone and Oxytocin on Term Human Myometrial Contractile Activity In Vitroxe2x80x9d, Obstetrics and Gynecology, 82: 532-38 (1993); OttoErich Brodde, xe2x80x9cBeta1 and Beta2 Adrenoceptors in the Human Heart: Properties, Function, and Alterations in Chronic Heart Failurexe2x80x9d, Pharmocological Review, Vol. 43, No. 2 (1991); Lanzara, R. xe2x80x9cA Novel Bio-physical Model for Receptor Activationxe2x80x9d Dept. of Allied Health Sci., CUNY, NY, N.Y. and Bio-Balance Inc., NY, N.Y.; and, Lanzara, R. xe2x80x9cWeber""s Law Modeled by the Mathematical Description of a Beam Balancexe2x80x9d, Mathematical Biosciences, 122: 89-94 (1994) are incorporated herein by reference.
I have solved the problem of determining the optimal concentration of an antagonist or inhibitor which is necessary to prevent cellular receptor desensitization without causing unnecessary and unwanted inhibition. My formulation combines a competitive antagonist with an agonist for/of a particular receptor in a specific proportion that maximizes the receptor response to the agonist and maintains this maximum response. This formulation describes precisely the concentration of the antagonist relative to that of the agonist. This concentration is given by the dissociation constant of the antagonist, Ki, divided by the square root of one-half of the product of the two dissociation constants of the drug-agonist for the receptor. This is the fractional concentration of antagonist that is necessary to prevent any desensitization of the receptor. Higher concentrations of the antagonist may be used causing, however, more inhibition of the response. Lower concentrations of the antagonist may be used, but this would allow some desensitization to occur. Also, there is inherent in the aforementioned discoveries a method for calculating drug efficacy by utilization of easily identifiable biophysical parameters.
Additional to both in-vitro and in-vivo data gleaned from the incorporated references (Xin Fu, et al. and Otto-Erich Brodde, ibid.) I had performed in-vitro test on Guinea pig trachea, a widely used substitute tissue for pharmacologic research on human trachea, to determine the optimal composition of an antagonist (propranolol) which is mixed with an agonist (isoproterenol) in order to prevent receptor desensitization produced by a large concentration of said agonist (isoproterenol=25 xcexcM). Specifically, the experimental data and the calculated values were compared. The agreement of the experimental data with the calculated value for f=Ki/xcfx86 was within one and one-quarter percent (1.25%; calculated=0.0395 vs. experimental=0.04). This excellent result validated the method for calculating the optimal ratio agonist/antagonist compositions to prevent receptor desensitization. This was a specific test of this invention to determine the optimal ratio of propranolol to isoproterenol in the Guinea pig trachea and proves that there exists a maximally effective ratio which finds utility in its ability to prevent agonist-induced drug desensitization.